KR20110101488A - Olanzapine xinafoate and the use thereof - Google Patents

Abstract

The present invention relates to an olanzapine ginapoate salt, a preparation method thereof, and a preparation and a pharmaceutical composition containing the same as an active ingredient, and more particularly, the step of reacting an olanzapine ginapoate salt and olanzapine with ginapoate in an organic solvent. It relates to a method for preparing olanzapine ginapoate salt, comprising olanzapine gnapoate salt, a preparation for parenteral administration consisting of diluents and excipients and a pharmaceutical composition containing olanzapine ginapoate as an active ingredient. The present invention provides an olanzapine ginapoate salt, a preparation method thereof, and a preparation and pharmaceutical composition containing the same as an active ingredient. The salts, preparations and compositions of the present invention are sustained in vivo for at least 4 weeks after administration to reduce the frequency of administration to patients and are effective at maintaining long term effective concentrations in the blood.

Description

Olanzapine xinafoate and the use thereof

The present invention relates to an olanzapine ginapoate salt, a preparation method thereof, and a preparation and a pharmaceutical composition containing the same as an active ingredient, and more particularly, the step of reacting an olanzapine ginapoate salt and olanzapine with ginapoate in an organic solvent. It relates to a method for preparing olanzapine ginapoate salt, comprising olanzapine gnapoate salt, a preparation for parenteral administration consisting of diluents and excipients and a pharmaceutical composition containing olanzapine gnapoate salt as an active ingredient.

Today, many antipsychotic drugs have been developed and used to treat central nervous system disorders or severe mental conditions. However, these drugs often cause side effects, with only 40% to 80% of all drug users responding only partially or not.

Olanzapine is a yellow crystalline solid that is almost insoluble in water and is widely used for the treatment of diseases of the central nervous system. Provided primarily by oral administration, to date, more than 5.6 million patients have been treated with olanzapine. Olanzapine is an antagonist of dopamine at the D-1 and D-2 receptors, and is also an antimuscarinic, anti-cholinergic, antagonist at the 5HT-2 receptor site. In addition, this compound has antagonist activity in alpha-receptors activated by noradrenaline. This activity is useful for treating mental conditions such as schizophrenia, schizophrenic disorders, and acute mania, because the compounds have a potential neuroleptic effect with relaxation, anxiety relief, or anti-vomiting. It is known to be effective in treating mild anxiety when administered in small doses.

Mental illnesses are not obedient and it is difficult to assess whether they are taking the right amount of medication. In addition, in some cases these patients are difficult to treat due to the overactive, confused, or rejective excited states they represent. Moreover, other underlying diseases besides psychosis such as postoperative delirium, behavioral disorders associated with mental retardation, emotional disorders, adaptation disorders, personality disorders, anxiety disorders can also induce the patient to be excited.

In this case, parenteral administration of antipsychotics is desirable when oral administration of the drug to the patient is impossible or its consistency is not reliable. However, frequent injections are not recommended for patients requiring long-term treatment due to the nature of the disease.

Therefore, in order to lower the frequency of administration, and to consistently administer the appropriate amount of drug and to evaluate its compliance, it is desirable to formulate the drug into a form that is capable of continuous drug release in the blood for a long time and can be administered intramuscularly.

In general, the method used for delaying the release of the drug is to prepare the active drug material in ester form, but in the case of olanzapine, the formation of the ester product is not easy. In addition, olanzapine is a metastable drug, which has a poor discoloration tendency, and is particularly susceptible to hydrolysis in a solution or a wet environment even at room temperature or refrigerated.

Therefore, there is an urgent need to develop a type of formulation that can guarantee the homogeneity and stability of the final formulation and effectively delay the release of olanzapine.

Accordingly, the present inventors have been studying how to reduce the frequency of drug administration of olanzapine and prolong the effective concentration maintenance period in vivo, and found that the concentration of olanzapine in blood persists when olanzapine is attached to poorly soluble salts and is pharmaceutically acceptable. Olanzapine salt can be prepared as a parenteral administration, and the olanzapine ginapoate salt can be used as an injection, and found that the effective concentration in vivo is maintained for a long time when the administration was completed, the present invention was completed.

Therefore, an object of the present invention is to provide an olanzapine ganpoate salt of the formula (1).

<Formula 1>

It is another object of the present invention to provide a method for preparing olanzapine ginafoate salt, which comprises reacting olanzapine with ginapoate in an organic solvent.

Another object of the present invention is to provide a preparation for parenteral administration comprising at least one pharmaceutically acceptable carrier, diluent, or excipient and olanzapine ginafoate salt as active ingredient.

Another object of the present invention is anxiety, schizophrenia, schizophrenia, mild anxiety, gastrointestinal disorders, acute mania, bipolar mania, bipolar disorder, containing olanzapine ginapoate salt as an active ingredient, Seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, psychosis, diabetic nerve pain, stop smoking and It is to provide a pharmaceutical composition for treating a condition selected from the group consisting of depression.

In order to achieve the above object, the present invention provides an olanzapine ganpoate salt of the formula (1).

<Formula 1>

In order to achieve another object of the present invention, the present invention provides a method for preparing olanzapine ginapoate salt comprising the step of reacting olanzapine with ginapoate in an organic solvent.

To achieve another object of the present invention, the present invention provides a formulation for parenteral administration comprising at least one pharmaceutically acceptable carrier, diluent, or excipient and olanzapine ginapoate salt as active ingredient.

In order to achieve another object of the present invention, the present invention is an anxiety, schizophrenia, schizophrenia, mild anxiety, gastrointestinal disorders, acute mania, bipolar mania, containing olanzapine ginapoate salt as an active ingredient, Bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, psychosis, diabetic nerve pain nerve pain), smoking cessation, and depression.

Hereinafter, the content of the present invention will be described in more detail.

The present invention provides a novel olanzapine ginapoate salt of the formula (1).

<Formula 1>

The olanzapine ginapoate salt of the present invention is a novel salt of olanzapine that can be controlled for release rate and can be used for intramuscular administration or subcutaneous administration.

In the olanzapine ginapoate salt of the present invention, ginafoate may be derived from 1-hydroxy-2-naphthoic acid.

When the olanzapine ginapoate salt of the present invention is crystallized from anhydride, it has a crystal structure characteristically showing the distance between crystal planes or diffraction angles of Table 1 in the X-ray diffractogram.

X-ray Diffraction Patterns of Olanzapine Ginapoate number 2Theta Between crystals
Distance (d) Relative Strength (I / Io) number 2Theta Between crystals
Distance (d) Relative Strength (I / Io) One 4.1800 21.1193 0.7 17 23.5000 3.7826 37.5 2 7.7000 11.4718 4.5 18 24.2200 3.6718 52.1 3 8.1800 10.8003 1.3 19 25.2399 3.5256 5.1 4 9.8000 9.0180 5.7 20 25.9600 3.4294 14.4 5 10.9400 8.0808 6.1 21 26.8800 3.3141 7.1 6 12.4200 7.1210 8.1 22 28.4200 3.1379 30.1 7 13.2800 6.6613 0.5 23 29.7400 3.0016 15.2 8 14.2000 6.2321 35.5 24 30.8400 2.8970 11.7 9 15.2800 5.7937 91.4 25 32.0200 2.7928 6.5 10 16.3600 5.4136 47.8 26 34.1000 2.6271 5.7 11 17.3400 5.1099 4.3 27 34.9400 2.5658 8.1 12 18.3400 4.8335 15.6 28 35.7400 2.5102 0.7 13 19.9600 4.4446 39.6 29 36.6800 2.4480 10.1 14 20.9000 4.2468 100.0 30 37.3000 2.4087 6.3 15 21.6000 4.1108 52.3 31 38.8800 2.3144 8.1 16 22.6800 3.9174 49.4 32 39.3800 2.2862 2.5

The term 2theta or 2θ refers to the peak position based on the experimental setup of the X-ray diffraction experiment and is the common abscissa unit in the diffraction pattern. The experimental apparatus records the reflected light at an angle of 2 theta when the reflection diffracts when the incoming light forms an angle between the constant lattice plane and theta [theta]. The unit of the interplanar spacing is Angstroms.

The olanzapine ginapoate salt of the present invention exhibits one melting point endothermic peak (about 226.4 J / g) having a starting point of about 203.1 ° C. and a minimum of about 205.3 ° C. in a differential scanning calorimetry (heating rate of 10 ° C./min).

The olanzapine ginapoate salt of the present invention maintains a blood concentration of at least 2 weeks, preferably at least 4 weeks when administered in vivo.

The olanzapine ginapoate salt having the above characteristics can be prepared by reacting olanzapine with ginapoate in an organic solvent.

Specifically, the olanzapine ginapoate salt may be prepared by reacting an olanzapine of Formula 2 with gnapoate of Formula 3 in an organic solvent having no adverse effect on the formation of the salt, and filtering and drying the resulting crystals. Can be.

Olanzapine of formula (2) and ginafoate of formula (3) may be isolated and purified from nature, used commercially, or prepared by chemical synthesis methods known in the art.

<Formula 2>

<Formula 3>

Organic solvents that can be used in the preparation method of the present invention include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, preferably ethanol.

Specifically, it is possible to dissolve the olanzapine at a rate of 10 ml to 50 ml of ethanol per 1 g of olanzapine, to dissolve gnapoate at a ratio of 10 ml to 50 ml of ethanol per 1 g of napophosphate, and to mix and precipitate them. The ratio of olanzapine to napopoate may be in a ratio of 0.5 to 2 mole (mole) of napozaate per 1 mole (mol) of olanzapine, preferably in a ratio of 0.8 to 1.5 mole (mol), and most preferably It can be set as the ratio of 1.0-1.2 mol.

When dissolving olanzapine and ginapoate, the temperature is preferably 10 ° C. to 40 ° C., and may be precipitated by cooling to −10 ° C. to 20 ° C. after mixing. The resulting crystals may be dried in a vacuum, reduced pressure or atmospheric pressure at a temperature of 10 ° C to 40 ° C.

The production method of the present invention can obtain the olanzapine ganpoate salt in high yield.

The olanzapine ginapoate salt of the present invention prepared as described above is poorly soluble and the concentration of the olanzapine gnapoate salt in the blood is prolonged for a long time, so anxiety, schizophrenia, schizophrenia, mild anxiety, gastrointestinal disorders, acute mania, Bipolar mania, bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, psychosis It can be used as an active ingredient of a pharmaceutical composition for treating a condition selected from the group consisting of diabetic nerve pain, stop smoking and depression.

Therefore, the present invention is an anxiety, schizophrenia, schizophrenia, mild anxiety, gastrointestinal disorders, acute mania, bipolar mania, bipolar disorder, seizure seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, psychosis, diabetic nerve pain, stop smoking and depression Provided is a pharmaceutical composition for treating a condition selected from the group consisting of:

The pharmaceutical composition according to the present invention may contain the olanzapine ginapoate salt alone or may further contain one or more pharmaceutically acceptable carriers, excipients or diluents.

Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. In addition, it may include a variety of drug delivery materials used for oral administration to the peptide formulation. In addition, carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. The pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent and the like in addition to the above components. Other pharmaceutically acceptable carriers may be referred to those described in the following documents (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

The composition of the present invention may be administered to any mammal, including humans. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. Can be.

Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a prescription generally known in all pharmaceutical chemistries.

The total effective amount of olanzapine ginapoate salt of the present invention may be administered to a patient in a single dose, and may be administered by a fractionated treatment protocol that is administered in multiple doses for long periods of time. have. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease. Preferably the preferred total dose of olanzapine ginapoate salt of the present invention may be about 0.01 μg to 100 mg, most preferably 0.1 μg to 10 mg per kg of patient body weight per day. However, the dose of olanzapine gnapoate salt is effectively administered to the patient in consideration of various factors such as the age, weight, health condition, sex, severity of the disease, diet and excretion rate, as well as the route of administration and frequency of treatment of the pharmaceutical composition. Since the amount is determined, those who have ordinary knowledge in the art should consider the olanzapine ginapoate salt for anxiety, schizophrenia, schizophrenia, mild anxiety, gastrointestinal disorders, acute mania and bipolar mania. mania, bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, psychosis, diabetic nerve Appropriate effective dosages for particular uses as prevention or treatment of diabetic nerve pain, stop smoking and depression You can decide. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.

On the other hand, the present invention provides a formulation for parenteral administration comprising at least one pharmaceutically acceptable carrier, diluent, or excipient and olanzapine ginafoate salt as active ingredient.

Carriers may include water, suitable oils, saline, aqueous glucose and glycols, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.

Parenteral administration as used herein is not limited to this, but may be intravenous, intramuscular, intraarterial, transdermal, subcutaneous, intraperitoneal, intranasal, enteral or topical administration.

Formulations for parenteral administration may be formulated in the form of injections, oils, aerosols and nasal inhalants by methods known in the art and preferably may be injections.

When prepared in the form of injectables, it is preferred that the composition in the form of a solution or suspension is sterile and isotonicized with blood. When a composition in the form of such a solution, emulsion, suspension or substantially homogeneous aqueous solution is prepared, various diluents known in the art can be used. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In such cases, the formulations of the present invention may further contain saline, glucose or glycerin in an amount sufficient to maintain isostatic pressure with the blood. In addition, the pharmaceutical compositions may also include conventional solubilizers, buffers, levelers, pH adjusters, stabilizers or solubilizers. Such injections can be lyophilized.

In addition, other conventional excipients such as glycerin, propylene glycol, polysorbate 20, polysorbate 40, stearate, carboxymethyl cellulose, polyvinyl pyrrolidone and sodium lauryl sulfate may be added to the formulations of the present invention.

Preferably the excipient of the present invention may be carboxymethyl cellulose or polysorbate 20.

The preparation of the present invention can be parenterally administered olanzapine ginapoate salt, and preferably can maintain blood concentration of olanzapine gnapoate salt for 2 weeks more preferably 4 weeks or more. The formulations of the present invention are injectable at 2 ml or less via a 20 gauge needle or smaller needle.

In an embodiment of the present invention, 4.69 g (15 mmol) of olanzapine (Olanzapine, 99%, FormV, Cipla Ltd. India) is dissolved in 150 ml of ethanol, and ginafoate (99%, Sigma-Aldrich Co., USA). 3.11 g (16.5 mmol) was separately dissolved in 60 ml of ethanol, and the two were slowly mixed, followed by slowly cooling for 2 hours to prepare an olanzapine ginapoate salt (see Example 1).

In another embodiment of the present invention, the structure of the olanzapine phosphoate salt of the present invention was confirmed by X-ray diffraction analysis, nuclear magnetic resonance analysis, mass spectrometry, scanning microscope analysis and differential scanning calorimetry.

As a result, it was confirmed that the olanzapine phosphoate salt of the present invention had a melting point of 205.3 ° C., an X-ray diffraction pattern as shown in FIG. 1, a crystal structure as shown in FIG. 2, and a structure represented by the following Chemical Formula 1 (Example 2).

<Formula 1>

In another embodiment of the present invention, the pharmaceutical properties such as dispersibility, injectable and blood concentration persistence of the olanzapine ginapoate salt of the present invention were tested.

As a result, it was confirmed that the olanzapine ginapoate salt of the present invention was well dispersed in a diluent and well inhaled and dispersed in a syringe using a 20G needle.

In addition, the olanzapine ginapoate salt of the present invention was injected into the experimental animals and the residual concentration in the blood was measured by time, and as a result, it was confirmed that the olanzapine gnapoate salt of the present invention remained in the effective concentration in the blood even after 4 weeks ( See Example 3).

As described above, the present invention provides an olanzapine phosphoate salt, a preparation method thereof, and a preparation and a pharmaceutical composition containing the same as an active ingredient. The salts, preparations and compositions of the present invention are sustained in vivo for at least 4 weeks after administration to reduce the frequency of administration to patients and are effective at maintaining long term effective concentrations in the blood.

1 shows the X-ray diffraction pattern of olanzapine phosphoate salt.
Figure 2 is a scanning electron micrograph of olanzapine napopoate salt.
Figure 3 is a result of performing differential scanning calorimetry (DSC) for olanzapine ganpoate salt (diagram).
Figure 4 is a graph of the result of the blood concentration persistence comparison test of olanzapine ganpoate salt. 4 is a linear scale of the concentration of olanzapine ginapoate salt in blood (▲: blood concentration of olanzapine free base as a control; blood: concentration of olanzapine ginapoate salt).
Figure 5 is a graph of the result of the blood concentration persistence comparison test of olanzapine ganpoate salt. 5 is a log scale of the concentration of olanzapine ginapoate salt in the blood (▲: blood concentration of the olanzapine free base control group; ●: blood concentration of olanzapine gnapoate salt).

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

&Lt; Example 1 >

Preparation of olanzapine xinafoate salt

4.69 g (15 mmol) of olanzapine (Olanzapine, 99%, FormV, Batch.No.B80343, Cipla Ltd., India) is completely dissolved in 150 ml of ethanol (HPLC grade, 99.8%), and ginafoate (99%, Batch) No. 07221BJ Sigma-Aldrich Co., USA) 3.11 g (16.5 mmol) was completely dissolved in 60 ml of ethanol separately, and the two were slowly mixed, and then cooled slowly for 2 hours to precipitate a solid. After the solid precipitated and washed with ethanol cooled to 10 ℃ or less after the filter and dried overnight at room temperature, vacuum.

As a result, 7.16 g of olanzapine xinafoate salt was obtained at a yield of 95%.

<Example 2>

Structural Analysis of Olanzapine xinafoate Salts

<2-1> X-ray diffraction analysis

X-ray diffraction patterns for the olanzapine phosphoate salt were collected using an X-ray diffractometer (M18XHF22, MacScience, Japan) using a 1.54056 파장 wavelength light source.

As a result, it was confirmed that the olanzapine phosphoate salt of the present invention has a pattern as shown in [Fig. 1] or [Table 1].

<2-2> Nuclear Magnetic Resonance (NMR) Analysis

The structure of the olanzapine phosphoate salt was analyzed using a nuclear magnetic resonance spectroscopy (FT-NMR UNTY 300, Varian, USA).

The analysis results are as follows.

Olanzapine xianafoate: Yield 95%; 1 H NMR (300 MHz, CDCl ₃ ): δ 2.28 (d, 3H), 2.68 (s, 3H), 3.04 (m, 4H), 3.43-3.53 (m, 4H), 6.40 (d, 1H), 6.70- 6.72 (m, 1H), 6.83-6.89 (m, 3H), 7.08 (d, 1H), 7.38-7.53 (m, 2H), 7.73-7.78 (m, 3H), 8.20-8.23 (d, 1H)

<2-3> Scanning electron microscope analysis

The outer shape of the olanzapine ginapoate salt of the present invention was observed using an S-3000N scanning electron microscope (HITACHI, Japan).

As a result, the crystals of olanzapine ginafoate salt having the same shape as in FIG. 2 were confirmed.

<2-4> Differential Scanning Calorimetric Analysis (DSC)

Differential scanning calorimetry for olanzapine ginapoate salts was performed using differential scanning calorimetry (DSC7, PERKIN ELMER, USA). The sample was equilibrated at 30 ° C. and then heated at a rate of 10 ° C./min under a nitrogen purge and finally up to 250 ° C.

DSC thermogram analysis of the olanzapine ganpoate salt As shown in [Fig. 3] it was confirmed that the olanzapine ganpoate salt has a melting point in the range of about 202 ~ 207 ℃. That is, the onset of melting is about 203.1 ° C. and the melting point peak is about 205.3 ° C. DSC analysis confirmed that the olanzapine ginapoate salt of the present invention was a high melt solid having a melting start point of about 203.1 ° C. and a melting point peak of about 205.3 ° C.

< Example  3>

Olanzapine Of lanzapine xinafoate salt  Characterization

<3-1> dispersibility and Scanning  exam

In order to determine whether the olanzapine novel salt of the present invention can be used as an injection, it was tested whether the synthesized olanzapine ginapoate salt was dispersed in an aqueous dispersion and then injected into a syringe.

As an aqueous dispersion, a solution containing 1% carboxymethyl cellulose (CMC) and 0.05% polysorbate20 in saline (0.9% NaCl) was used. Gauge) needle was used.

20 mg of olanzapine phosphoate salt powder was placed in a 1.5 ml tube, and 0.2 ml of an aqueous dispersion was added and suspended to make a 10% (w / v) suspension. It was sucked into the syringe and flushed to see if the two movements were smooth.

As a result, in the case of other olanzapine salts being developed together, only the dispersion liquid was sucked up and the salt particles remained in the lump, but the olanzapine ginapoate salt of the present invention was well dispersed in the aqueous dispersion and confirmed that injection through the syringe was possible ( See Table 2).

Dispersibility and Injectability of Olanzapine Novel Salts Formulation result Remarks Olanzapine Ginapoate Salt (OX) + Good dispersibility and scanning

<3-2> Olanzapine Ginapoate salt  Blood concentration sustainability comparison test (pharmacokinetic analysis ( Pharmacokinetic analysis ))

In order to determine the persistence of blood concentration of olanzapine ganpoate salt, experimental animals were injected with olanzapine ganpoate salt of the present invention and its duration was measured.

SD rats (Sprague-Dawley rat, male) were used as experimental animals, and olanzapine free base was tested as a control.

As a control, 40 mg of olanzapine was suspended in 0.35 ml of the aqueous dispersion used in Example 3-1 and injected into the rear thigh muscle at a dose of 40 mg / kg.

The experimental group suspended 30 mg of olanzapine ginapoate salt in 0.3 ml of the aqueous dispersion used in Example 3-1 and injected it into the posterior thigh muscle at a dose of 40 mg / kg.

Thereafter, blood was collected from the orbital vein according to a predetermined time and analyzed by LC / MS / MS (API4000, AB MDS Sciex). The high performance liquid chromatography (HPLC) used was Nanospace SI-2 (Shiseido, Japan) and the column was Capcell pak MG3 (5 μm, 2.0 × 50.0 mm, Shiseido, Japan). The mobile phase used acetonitrile: 10 mM ammonium acetate = 6: 4 mixed solution and the flow rate was measured to 0.25ml / min. Sample dose was 10 ul.

The control group and the experimental group were all tested three animals and used the average.

As a result, as shown in [FIG. 4], [FIG. 5], and [Table 3], in the case of a control group, the maximum concentration concentration time (Tmax) of blood was 1 hour, and the maximum concentration of blood (Cmax) was 218 ng / ml, and 14 days. After the concentration of 0.33 ng / ml, the olanzapine ginapoate salt of the present invention has a Tmax of 2 to 6 hours, a Cmax of 125 ng / ml, after 5.23 ng / ml, and after a lapse of 28 days, 0.52 It was confirmed that the concentration of ng / ml.

As a result, it was confirmed that the olanzapine ginapoate salt of the present invention can be used as an injection that can maintain the blood concentration of olanzapine for a long time for 4 weeks.

Comparison of PK Results of Olanzapine Free Base and Olanzapine Ginapoate Salts Olanzapine free base Olanzapine xinafoate Tmax (hr) One 2 ~ 6 Cmax (ng / ml) 218 125 Blood concentration after 14 days (ng / ml) 0.33 5.23 (after 16 days) Blood concentration after 28 days (ng / ml) - 0.52

< Manufacturing example  1> Injection

Olanzapine Ginapoate Salt 20mg

0.2 ml of aqueous dispersion (sterile distilled water for injection with 0.9% NaCl, 1% carboxymethyl cellulose, 0.05% polysorbate 20)

The components were mixed and then prepared according to a conventional injection method.

Accordingly, the present invention provides an olanzapine ginapoate salt, a preparation method thereof, and a preparation and pharmaceutical composition containing the same as an active ingredient. Salts, formulations and compositions of the present invention are continuously released in vivo for at least 4 weeks after administration to reduce the frequency of administration to the patient, and has the effect of maintaining an effective concentration in the blood for a long time, and thus has high industrial applicability.

Claims (8)

Olanzapine ginapoate salt of the formula (1).

<Formula 1>

The olanzapine ginapoate salt according to claim 1, having an X-ray diffraction pattern represented by the interplanar distances shown in Table 1 below.
TABLE 1

A method for preparing olanzapine ginapoate salt comprising reacting olanzapine with ginapoate in an organic solvent.
The method of claim 3, wherein the organic solvent is selected from the group consisting of ethanol, ethyl acetate, methanol, tetrahydrofuran, isopropyl alcohol, and acetone.
The method of claim 3, wherein the molar ratio of the olanzapine and ginapoate is 1: 1.0 to 1.2.
A formulation for parenteral administration comprising at least one pharmaceutically acceptable carrier, diluent, or excipient and olanzapine ginafoate salt as active ingredient.
The formulation according to claim 6, wherein the excipient is glycerin, propylene glycol, stearate, carboxymethyl cellulose, polyvinyl pyrrolidone, sodium lauryl sulfate, polysorbate 20, polysorbate 40.
Anxiety, schizophrenia, schizophrenia, mild anxiety, gastrointestinal disorders, acute mania, bipolar mania, bipolar disorder, seizure containing olanzapine ginapoate salt of claim 1 as an active ingredient ), Obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, psychosis, diabetic nerve pain, stop smoking and depression A pharmaceutical composition for treating a condition selected from the group.

Images